Reduced Exposure Study Using CHTP 1.0 During 5 Days in Confinement.

• Sponsor: Philip Morris Products S.A. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02503254
• Collaborator: (none)
• Enrollment: 85
• Location: 1
• Arms: 2
• Duration (Months): 8
• Patients Per Site Per Month: 10.6

Study Details

Study Description

Brief Summary

The overall goal of the study is to demonstrate the reduction of biomarkers of exposure (BoExp) to selected harmful and potentially harmful constituents (HPHCs) in adult smokers switching for 5 days from conventional cigarette (CC) to Carbon Heated Tobacco Product 1.0 (CHTP 1.0) as compared to smokers continuing to use CC.

Condition or Disease	Intervention/Treatment	Phase
Smoking	Other: CHTP 1.0; Other: Conventional Cigarette (CC)	N/A

Study Design

• Study Type: Interventional
• Actual Enrollment: 85 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: A Randomized, Controlled, Open-label, 2-arm Parallel Group, Single Center Study to Demonstrate Reductions in Exposure to Selected Smoke Constituents in Healthy Smokers Switching to the Carbon Heated Tobacco Product 1.0 (CHTP 1.0) Compared to Continuing to Use Conventional Cigarettes During 5 Days in Confinement.
• Study Start Date: Jul 1, 2015
• Actual Primary Completion Date: Sep 1, 2015
• Actual Study Completion Date: Mar 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CHTP 1.0 Ad libitum use of the Carbon Heated Tobacco Product 1.0 (CHTP 1.0) for 5 days in confinement	Other: CHTP 1.0; CHTP 1.0 ad libitum for 5 days in confinement
Active Comparator: Conventional cigarette (CC) Ad libitum use of subject's own preferred brand of CC for 5 days in confinement	Other: Conventional Cigarette (CC); Subject's own preferred brand of CC ad libitum for 5 days in confinement

Outcome Measures

Primary Outcome Measures

1. Concentration of Monohydroxybutenyl Mercapturic Acid (MHBMA) [5 days]

   Concentrations measured on Day 5 in urine, adjusted for creatinine. Geometric Least Squares (LS) means are provided as descriptive statistics.

2. Concentration of 3-hydroxypropylmercapturic Acid (3-HPMA) [5 days]

   Concentrations measured on Day 5 in urine, adjusted for creatinine. Geometric Least Squares means are provided as descriptive statistics.

3. Concentration of S-phenylmercapturic Acid (S-PMA) [5 days]

   Concentrations measured on Day 5 in urine, adjusted for creatinine. Geometric Least Squares means are provided as descriptive statistics.

4. Levels of Carboxyhemoglobin (COHb) [5 days]

   % COHb blood measurements performed in the evening of Day 5, expressed as % of saturation of hemoglobin. Geometric Least Squares means are provided as descriptive statistics.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Subject is aged ≥ 21 years.

• Subject is Caucasian.

• Subject is healthy, as judged by the Investigator.

• Subject smokes at least 10 commercially available non-menthol CCs per day (no brand restrictions) for at least the last 6 weeks prior to admission, based on self-reporting.

• Subject has smoked at least for the last 3 years.

• Subject does not plan to quit smoking in the next 3 months.

Exclusion Criteria:

• As per Investigator judgment, the subject cannot participate in the study for any reason (e.g., medical, psychiatric, and/or social reason).

• Subject has received medication within 14 days or within 5 half-lives of the medication (whichever is longer), which has an impact on cytochrome P450 1A2 (CYP1A2) or cytochrome P450 2A6 (CYP2A6) activity.

• Female subject is pregnant or breast feeding.

• Female subject does not agree to use an acceptable method of effective contraception.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	BioVirtus Research Site Sp. z o.o.	Kajetany		Poland	05-830

Sponsors and Collaborators

• Philip Morris Products S.A.

Investigators

• Study Chair: Christelle Haziza, PhD, Philip Morris Products S.A.
• Principal Investigator: Katarzyna Jarus-Dziedzic, MD, PhD, BioVirtus Research Site

Study Documents (Full-Text)

• Study Protocol - Jun 24, 2015
• Statistical Analysis Plan - Mar 21, 2016

More Information

Publications

None provided.

• Responsible Party: Philip Morris Products S.A.
• ClinicalTrials.gov Identifier: NCT02503254
• Other Study ID Numbers: P2R-REXC-06-EU; P2R-REXC-06-EU
• First Posted: Jul 20, 2015
• Last Update Posted: Mar 27, 2020
• Last Verified: Mar 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Philip Morris Products S.A.: Smoking; Modified risk tobacco product; Conventional cigarette; Reduced exposure; Confinement; Carbon Heated Tobacco Product

Study Results

Participant Flow

Recruitment Details	Study initiated (first subject screened): 04 July 2015 At admission (Day -3), all the subjects performed a product trial of the CHTP 1.0. During the baseline period, they continued smoking their single preferred brand of CC. Then, on Day -1, subjects were randomized to one of the two study arms (CHTP 1.0 or CC) in a 1:1 ratio.
Pre-assignment Detail	Enrolled and randomized population = 80 subjects 41 subjects in CHTP 1.0 arm 39 subjects in CC arm Number of subjects enrolled but NOT randomized (who tried the CHTP 1.0 at Day -3) = 5

Arm/Group Title	CHTP 1.0	Conventional Cigarette (CC)
Arm/Group Description	Ad libitum use of the Carbon Heated Tobacco Product 1.0 (CHTP 1.0) for 5 days in confinement	Ad libitum use of subject's own preferred brand of CC for 5 days in confinement
Period Title: Overall Study
STARTED	41	39
COMPLETED	41	39
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	CHTP 1.0	Conventional Cigarette (CC)	Total
Arm/Group Description	Ad libitum use of the Carbon Heated Tobacco Product 1.0 (CHTP 1.0) for 5 days in confinement	Ad libitum use of subject's own preferred brand of CC for 5 days in confinement	Total of all reporting groups
Overall Participants	41	39	80
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	34.1 (10.45)	32.7 (10.97)	33.5 (10.66)
Sex: Female, Male (Count of Participants)
Female	21 51.2%	20 51.3%	41 51.3%
Male	20 48.8%	19 48.7%	39 48.8%
International Organization for Standardization (ISO) nicotine level (Count of Participants)
≤ 0.6 mg	32 78%	34 87.2%	66 82.5%
> 0.6 to ≤ 1 mg	9 22%	5 12.8%	14 17.5%

Outcome Measures

1. Primary Outcome

Title	Concentration of Monohydroxybutenyl Mercapturic Acid (MHBMA)
Description	Concentrations measured on Day 5 in urine, adjusted for creatinine. Geometric Least Squares (LS) means are provided as descriptive statistics.
Time Frame	5 days

Outcome Measure Data

Analysis Population Description

The analysis was performed on the full analysis set (FAS) population. The FAS consisted of all the randomized subjects who had at least 1 post randomization product use experience (CHTP 1.0 or CC) and had at least 1 non-safety assessment.

Arm/Group Title	CHTP 1.0	Conventional Cigarette (CC)
Arm/Group Description	Ad libitum use of the Carbon Heated Tobacco Product 1.0 (CHTP 1.0) for 5 days in confinement	Ad libitum use of subject's own preferred brand of CC for 5 days in confinement
Measure Participants	41	39
Least Squares Mean (95% Confidence Interval) [pg/mg creat]	327.08	1903.61

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CHTP 1.0, Conventional Cigarette (CC)
	Comments	The hypothesis to be tested is that the geometric mean level on Day 5 of the biomarker of exposure for CHTP 1.0 is lower relative to CC. Analysis of the BoExp was conducted on the natural log scale in order to test the following hypothesis (one sided test with 2.5% type I error probability): Null hypothesis (H0): m1≥m2 Alternative hypothesis (H1): m1<m2 Where m1 and m2 are the geometric means of the BoExp levels on Day 5 for CHTP 1.0 and CC, respectively.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<.001
	Comments	The primary endpoints were tested using a multiple testing procedure to preserve the overall alpha level by simultaneously testing the endpoints using a closed procedure with each test performed at a two-sided alpha level of 5%.
	Method	ANCOVA
	Comments	ANCOVA model on MHBMA levels with product, sex, cigarette consumption, and baseline value as covariates.
Method of Estimation	Estimation Parameter	Geometric LS Mean Reduction
	Estimated Value	82.82
	Confidence Interval	(2-Sided) 95%; 78.79 to 86.09
	Parameter Dispersion	Type: Value:
	Estimation Comments	Geometric LS Mean Reduction = 100 - (CHTP 1.0 : CC ratio) Expressed as %

2. Primary Outcome

Title	Concentration of 3-hydroxypropylmercapturic Acid (3-HPMA)
Description	Concentrations measured on Day 5 in urine, adjusted for creatinine. Geometric Least Squares means are provided as descriptive statistics.
Time Frame	5 days

Outcome Measure Data

Analysis Population Description

The analysis was performed on the full analysis set (FAS) population. The FAS consisted of all the randomized subjects who had at least 1 post randomization product use experience (CHTP 1.0 or CC) and had at least 1 non-safety assessment.

Arm/Group Title	CHTP 1.0	Conventional Cigarette (CC)
Arm/Group Description	Ad libitum use of the Carbon Heated Tobacco Product 1.0 (CHTP 1.0) for 5 days in confinement	Ad libitum use of subject's own preferred brand of CC for 5 days in confinement
Measure Participants	41	39
Least Squares Mean (95% Confidence Interval) [ng/mg creat]	464.27	1272.96

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CHTP 1.0, Conventional Cigarette (CC)
	Comments	The hypothesis to be tested is that the geometric mean level on Day 5 of the biomarker of exposure for CHTP 1.0 is lower relative to CC. Analysis of the BoExp was conducted on the natural log scale in order to test the following hypothesis (one sided test with 2.5% type I error probability): Null hypothesis (H0): m1≥m2 Alternative hypothesis (H1): m1<m2 Where m1 and m2 are the geometric means of the BoExp levels on Day 5 for CHTP 1.0 and CC, respectively
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The primary endpoints were tested using a multiple testing procedure to preserve the overall alpha level by simultaneously testing the endpoints using a closed procedure with each test performed at a two-sided alpha level of 5%.
	Method	ANCOVA
	Comments	ANCOVA model on 3-HPMA levels with product, sex, cigarette consumption, and baseline value as covariates.
Method of Estimation	Estimation Parameter	Geometric LS Mean Reduction
	Estimated Value	63.53
	Confidence Interval	(2-Sided) 95%; 59.55 to 67.12
	Parameter Dispersion	Type: Value:
	Estimation Comments	Geometric LS Mean Reduction = 100 - (CHTP 1.0 : CC ratio) Expressed as %

3. Primary Outcome

Title	Concentration of S-phenylmercapturic Acid (S-PMA)
Description	Concentrations measured on Day 5 in urine, adjusted for creatinine. Geometric Least Squares means are provided as descriptive statistics.
Time Frame	5 days

Outcome Measure Data

Analysis Population Description

The analysis was performed on the full analysis set (FAS) population. The FAS consisted of all the randomized subjects who had at least 1 post randomization product use experience (CHTP 1.0 or CC) and had at least 1 non-safety assessment.

Arm/Group Title	CHTP 1.0	Conventional Cigarette (CC)
Arm/Group Description	Ad libitum use of the Carbon Heated Tobacco Product 1.0 (CHTP 1.0) for 5 days in confinement	Ad libitum use of subject's own preferred brand of CC for 5 days in confinement
Measure Participants	41	39
Least Squares Mean (95% Confidence Interval) [pg/mg creat]	352.39	2971.98

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CHTP 1.0, Conventional Cigarette (CC)
	Comments	The hypothesis to be tested is that the geometric mean level on Day 5 of the biomarker of exposure for CHTP 1.0 is lower relative to CC. Analysis of the BoExp was conducted on the natural log scale in order to test the following hypothesis (one sided test with 2.5% type I error probability): Null hypothesis (H0): m1≥m2 Alternative hypothesis (H1): m1<m2 Where m1 and m2 are the geometric means of the BoExp levels on Day 5 for CHTP 1.0 and CC, respectively.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<.001
	Comments	The primary endpoints were tested using a multiple testing procedure to preserve the overall alpha level by simultaneously testing the endpoints using a closed procedure with each test performed at a two-sided alpha level of 5%.
	Method	ANCOVA
	Comments	ANCOVA model on MHBMA levels with product, sex, cigarette consumption, and baseline value as covariates
Method of Estimation	Estimation Parameter	Geometric LS Mean Reduction
	Estimated Value	88.14
	Confidence Interval	(2-Sided) 95%; 86.46 to 89.62
	Parameter Dispersion	Type: Value:
	Estimation Comments	Geometric LS Mean Reduction = 100 - (CHTP 1.0 : CC ratio) Expressed as %

4. Primary Outcome

Title	Levels of Carboxyhemoglobin (COHb)
Description	% COHb blood measurements performed in the evening of Day 5, expressed as % of saturation of hemoglobin. Geometric Least Squares means are provided as descriptive statistics.
Time Frame	5 days

Outcome Measure Data

Analysis Population Description

The analysis was performed on the full analysis set (FAS) population: all randomized subjects who had at least 1 post randomization product use experience (CHTP 1.0 or CC) and had at least 1 non-safety assessment. However, due to sample issues such as clotting, COHb assessment results could not be generated for some of the subjects.

Arm/Group Title	CHTP 1.0	Conventional Cigarette (CC)
Arm/Group Description	Ad libitum use of the Carbon Heated Tobacco Product 1.0 (CHTP 1.0) for 5 days in confinement	Ad libitum use of subject's own preferred brand of CC for 5 days in confinement
Measure Participants	32	26
Least Squares Mean (95% Confidence Interval) [percentage of saturation of hemoglobin]	2.660	6.460

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CHTP 1.0, Conventional Cigarette (CC)
	Comments	The hypothesis to be tested is that the geometric mean level on Day 5 of the biomarker of exposure for CHTP 1.0 is lower relative to CC. Analysis of the BoExp was conducted on the natural log scale in order to test the following hypothesis (one sided test with 2.5% type I error probability): Null hypothesis (H0): m1≥m2 Alternative hypothesis (H1): m1<m2 Where m1 and m2 are the geometric means of the BoExp levels on Day 5 for CHTP 1.0 and CC respectively.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<.001
	Comments	The primary endpoints were tested using a multiple testing procedure to preserve the overall alpha level by simultaneously testing the endpoints using a closed procedure with each test performed at an alpha level of 2.5% one sided.
	Method	ANCOVA
	Comments	ANCOVA model on COHb levels with product, sex, cigarette consumption, and baseline value as covariates.
Method of Estimation	Estimation Parameter	Geometric LS Mean Ratio
	Estimated Value	58.83
	Confidence Interval	(2-Sided) 95%; 49.30 to 66.56
	Parameter Dispersion	Type: Value:
	Estimation Comments	Geometric LS Mean Reduction = 100 - (CHTP 1.0 : CC ratio) Expressed as %

Adverse Events

Time Frame	From the informed consent form signature until the end of the safety follow-up period, up to 58 days (including a screening period of up to 42 days, a 9-day confinement period followed by a 7-day safety follow-up period (7 days after discharge of the subject or early discontinuation)).
Adverse Event Reporting Description	The safety was assessed in the safety population, consisting of 85 subjects: 80 randomized subjects (41 in CHTP 1.0 and 39 in CC) and 5 subjects exposed to CHTP 1.0 during the product trial on Day -3 but not randomized.
Arm/Group Title	CHTP 1.0		Conventional Cigarette (CC)		Enrolled But Not Randomized
Arm/Group Description	Ad libitum use of the Carbon Heated Tobacco Product 1.0 (CHTP 1.0) for 5 days in confinement		Ad libitum use of subject's own preferred brand of CC for 5 days in confinement		Subjects who tried the CHTP 1.0 at Admission (Day -3) but were not randomized
All Cause Mortality
	CHTP 1.0		Conventional Cigarette (CC)		Enrolled But Not Randomized
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	CHTP 1.0		Conventional Cigarette (CC)		Enrolled But Not Randomized
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/41 (0%)		0/39 (0%)		1/5 (20%)
Injury, poisoning and procedural complications
Concussion	0/41 (0%)	0	0/39 (0%)	0	1/5 (20%)	1
Other (Not Including Serious) Adverse Events
	CHTP 1.0		Conventional Cigarette (CC)		Enrolled But Not Randomized
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	27/41 (65.9%)		14/39 (35.9%)		5/5 (100%)
Blood and lymphatic system disorders
Leukocytosis	2/41 (4.9%)	2	0/39 (0%)	0	1/5 (20%)	1
Gastrointestinal disorders
Nausea	0/41 (0%)	0	1/39 (2.6%)	1	1/5 (20%)	1
Vomiting	0/41 (0%)	0	0/39 (0%)	0	2/5 (40%)	2
General disorders
Vessel puncture site haematoma	0/41 (0%)	0	2/39 (5.1%)	2	0/5 (0%)	0
Hepatobiliary disorders
Hyperbilirubinaemia	0/41 (0%)	0	2/39 (5.1%)	2	1/5 (20%)	1
Injury, poisoning and procedural complications
Head injury	0/41 (0%)	0	0/39 (0%)	0	1/5 (20%)	1
Metabolism and nutrition disorders
Hypertriglyceridaemia	0/41 (0%)	0	2/39 (5.1%)	2	2/5 (40%)	2
Hyperkalaemia	0/41 (0%)	0	1/39 (2.6%)	1	1/5 (20%)	1
Hyperglycaemia	0/41 (0%)	0	0/39 (0%)	0	1/5 (20%)	1
Nervous system disorders
Headache	19/41 (46.3%)	21	9/39 (23.1%)	13	3/5 (60%)	3
Syncope	2/41 (4.9%)	2	1/39 (2.6%)	1	1/5 (20%)	1
Psychiatric disorders
Agitation	0/41 (0%)	0	0/39 (0%)	0	1/5 (20%)	1
Renal and urinary disorders
Leukocyturia	1/41 (2.4%)	1	0/39 (0%)	0	1/5 (20%)	1
Respiratory, thoracic and mediastinal disorders
Cough	13/41 (31.7%)	17	0/39 (0%)	0	0/5 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

We confirm we have the contractual provisions in place which specifies that in no event will the study site be allowed to disclose to any third party (or publicly release) any information obtained through the study without the CRO's prior written consent which in turn cannot provide such consent without Sponsor's approval unless such publication is made to satisfy regulatory requirements. The Intellectual Property rights and research results from the present study belongs to the Sponsor.